The primary objective of this project is to develop new agents for the treatment of childhood cancers with an emphasis on a more rational, targeted approach of drug development based on the current understanding of the molecular pathogenesis of human cancers. New molecularly targeted agents that are undergoing clinical development for adult cancers will be applied to childhood cancers based on the mechanism of action of the drug and the importance of the target in childhood cancers. In addition, novel cytotoxic agents are undergoing clinical evaluation. This work is performed through the Pharmacology and Experimental Therapeutics (P&ET) Section of the NCI POB. Examples of clinical trials ongoing and in development include: 1) The development of the raf kinase and receptor tyrosine kinase inhibitor sorafenib for children with refractory cancers and leukemias. A phase I trial of sorafenib conducted by the Children's Oncology Group (COG) Phase I Consortium with myself serving as protocol chair was recently completed. This study was expanded to determine the activity of sorafenib in children and young adults with refractory AML and FLT3-ITD mutations. Activity of sorafenib in this patient cohort has been observed, and a phase II study incorporating sorafenib into the upfront treatment for children with AML and FLT3ITD mutations is ongoing within the COG. In addition, we developed a phase II trial for select solid tumor strata, which is ongoing within the COG, and enrollment is nearing completion. Simultaneously we performed a phase I trial of sorafenib for children with neurofibromatosis type 1 (NF1) related tumors (see project 1). 2) The mTOR pathway is involved in the progression of human cancers and neurofibromatosis type 1 (NF1) related tumors, and clinical trials with mTOR inhibitors are ongoing, and will be pursued for both patient populations. For example, a multi-institutional clinical trial for patients with refractory sporadic or NF1 related malignant peripheral nerve sheath tumors (MPNST) with the mTOR inhibitor RAD001 in combination with the angiogenesis inhibitor bevacizumab is open for enrollment. This trial is receiving funding through a Department of Defense Clinical Trial Award to the Trial PI B. Widemann). Based on preclinical work from Dr. Karen Cichowski's laboratory, we also developed a phase I/II clinical trial of the mTOR inhibitor sirolimus in combination with the HSP90 inhibitor ganetespib for adults with refractory sarcomas and MPNST. We are currently performing preclinical studies in collaboration with several NCI investigators with the goal to develop a phase I trial with ganetespib for children with refractory cancers. 3) In addition, we are pursuing the clinical development of novel cytotoxic agents for children and young adults with refractory cancers. We recently completed a multi-institutional phase II trial of neoadjuvant chemotherapy for patients with high-grade, unresectable, chemotherapy nave malignant peripheral nerve sheath tumors (MPNST). MPNSTs are aggressive soft tissue sarcomas and are associated with poor outcome, particularly in individuals with NF1 (see project 1). A phase I clinical trial of satraplatin, a novel orally bioavailable platinum agent, is currently in development as a single institution phase I trial. Satraplatin demonstrates antitumor activity in preclinical models including cisplatin resistant models, and has shown activity in adult trials for several solid malignancies including prostate cancer. The dose-limiting toxicity of satraplatin is myelosuppression. Neurotoxicity and renal toxicity, which are associated with cisplatin and carboplatin, have not been described in patients receiving satraplatin. The lack of these toxicities and the preclinical and clinical activity provide a strong rationale for the development of satraplatin for children with refractory cancers. The pharmacokinetics and pharmacodynamics of drugs in clinical development will be studied and compared to results in adults. In collaboration with Drs. Helman and Grohar we have also developed a phase I/II trial of mithramycin, an anti-tumor antibiotic, which specifically inhibits the EWS/FLI1 fusion transcript, which is characteristic of Ewing sarcoma. This trial is ongoing and will determine the safety and pharmacokinetics of mithramycin in children and the activity of mithramycin in children and adults with Ewing sarcoma. 4) We are expanding our efforts into the development of clinical trials for rare cancers. In collaboration with the COG we have developed a phase I clinical trial of XL184 (cabozantinib) and oral RET and VEGFR and MET inhibitor. This trial is open to enrollment. These targets are important in pediatric malignancies and hereditary medullary thyroid carcinoma (MTC), for which we have an ongoing clinical trial with an oral RET inhibitor. Development of this trial will allow for patients with refractory MTC to enroll on another trial, which may provide benefit. In collaboration with Dr. Helman and Dr. Arnaldez we have also developed a phase II trial with vandetanib, a targeted agent, for children and adults with pediatric wild-type SDH deficient gastrointestinal stromal cell tumors. No effective medical treatment options for this rare cancer are available currently. This effort builds on findings made in the pediatric GIST clinic under leadership of Dr. Helman. 5) The development of effective therapies for children and young adults with hereditary medullary thyroid carcinoma (MTC) has been another goal. We recently published the results of our phase I/II trial of the RET and RTK inhibitor vandetanib in children and adolescents with MTC. Approximately 50% of the patients enrolled experienced a partial response, and most patients remain on treatment after multiple treatment cycles, Our phase I trial of XL184 provides a treatment option for patients who develop disease progression on vandetanib. In addition, we have developed a natural history trial for patients with MTC. Goals of this study, which ahs enrolled 17 patients, include to monitor the natural history of tumor and non tumor manifestations and to evaluate genomic changes in MTC tumor sampels which may predict for response or resistance to treatment .